US5830902A - Quinuclidine derivative having tricyclic hetero condensed ring - Google Patents

Quinuclidine derivative having tricyclic hetero condensed ring Download PDF

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US5830902A
US5830902A US08/894,549 US89454997A US5830902A US 5830902 A US5830902 A US 5830902A US 89454997 A US89454997 A US 89454997A US 5830902 A US5830902 A US 5830902A
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group
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quinuclidine
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Masahiko Isaka
Tsukasa Ishihara
Koyo Matsuda
Hirotoshi Kakuta
Hiroshi Moritani
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • This invention relates to a novel quinuclidine derivative having a tricyclic hetero condensed ring, a salt thereof, a hydrate thereof or a solvate thereof, which has a squalene synthase inhibiting action, and to a squalene synthase inhibitor which contains the compound as the active ingredient.
  • arteriosclerosis induces various diseases. For example, ischemic heart diseases induced by coronary arteriosclerosis have the highest mortality rate next to cancer in Japan, and it is known that cerebral infarction induced by cerebral arteriosclerosis is accompanied by serious secondary diseases such as difficulty of moving, dementia and the like. In addition, since these various diseases induced by arteriosclerosis have been increasing with the increase in aged population and the changes in the dietary life into European and American styles, great concern has been directed toward the development of on effective therapeutic agent.
  • Increase in the blood cholesterol level is considered important as a main causal factor of arteriosclerosis which is a degenerative disease of the artery.
  • Increase in the blood cholesterol firstly causes increase in blood lipid level and deposition of lipid on the inner membrane of large blood vessel, and the range and degree of these phenomena increase with the advance in years, finally causing ischemic heart diseases such as myocardial infarction, angina pectoris and the like, cerebral arteriosclerotic diseases such as cerebral infarction and the like and clinical symptoms such as aneurysm and the like.
  • ischemic heart diseases such as myocardial infarction, angina pectoris and the like
  • cerebral arteriosclerotic diseases such as cerebral infarction and the like
  • clinical symptoms such as aneurysm and the like.
  • the aforementioned known inhibitors aim at 3-hydroxymethylglutaryl coenzyme A reductase (hereinafter, to be referred to as HMG-CoA reductase) as the target enzyme, and this enzyme is located at a relatively early stage of the cholesterol biosynthesis system. Accordingly, it is possible that inhibition of the enzyme by the administration of the aforementioned agents may also induce inhibition of the synthesis of other important metabolic products such as dolichol, ubiquinone, isopentenyl tRNA, p21Ras, low molecular weight G protein and the like which are concerned in intracellular information transfer and cell growth (cf. Trends Biochem. Soc., vol. 4, p. 230 (1993), Cell, vol. 65, p. 1 (1991)).
  • HMG-CoA reductase 3-hydroxymethylglutaryl coenzyme A reductase
  • triparanol known as the inhibitor of an enzyme located at a downstream stage of the cholesterol biosynthesis system accumulates desmosterol which causes the cataracts.
  • an inhibitor which targets squalene synthase an enzyme positioned at a stage after branching into physiologically important metabolic products and before formation of lanosterol that becomes a causal substance for arteriosclerosis, will provide a cholesterol biosynthesis inhibitor which has more higher safety and does not cause inhibition of the synthesis of other metabolites and does not cause accumulation of toxic substances in the living body.
  • HMG-CoA reductase and squalene synthase are both down-regulated by sterol Faust, J. R., Goldstein, J. L. and Brown, M. S., Proc. Nat. Acad. Sci. USA, vol. 76, pp. 5018-5022 (1979)!.
  • sterol Faust J. R., Goldstein, J. L. and Brown, M. S., Proc. Nat. Acad. Sci. USA, vol. 76, pp. 5018-5022 (1979)!.
  • considerable induction of enzyme activity occurs when supply of sterol is blocked by inhibiting its activity, thus inevitably requiring increase of the dosage, while such an induction is small in the case of squalene synthase which therefore can bear efficient reduction of blood cholesterol level without increasing its dosage.
  • WO 93/15073 shows compounds by a general formula in which an azabicyclo ring such as of quinuclidine or the like is linked to an aromatic ring or hetero aromatic ring via an alkylene chain which may have one hetero atom or unsaturated bond.
  • an azabicyclo ring such as of quinuclidine or the like is linked to an aromatic ring or hetero aromatic ring via an alkylene chain which may have one hetero atom or unsaturated bond.
  • dibenzofuran are illustratively disclosed as compounds which have hetero aromatic rings, particularly tricyclic hetero condensed rings, and nothing is illustratively disclosed or suggested about other compounds having tricyclic hetero condensed rings. That is, only three compounds of ##STR2## are illustratively disclosed.
  • their use is calcium channel antagonist, and nothing is disclosed or suggested about the cholesterol biosynthesis inhibiting action or squalene synthase inhibiting action.
  • the object of the present invention is to provide cholesterol biosynthesis inhibitors, particularly a squalene synthase inhibitor represented by the following general formula (I) whose chemical structure is different from those of the prior art compounds and which is excellent in terms of markedly reduced side effects and higher safety, for example, showing less danger of inhibiting the synthesis of other metabolites and accumulating toxic substances in the living body.
  • a squalene synthase inhibitor represented by the following general formula (I) whose chemical structure is different from those of the prior art compounds and which is excellent in terms of markedly reduced side effects and higher safety, for example, showing less danger of inhibiting the synthesis of other metabolites and accumulating toxic substances in the living body.
  • the object of the present invention is to provide a medicine having squalene synthase inhibiting activity, which contains a novel quinuclidine derivative having a tricyclic hetero condensed ring, represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as its active ingredient, or a pharmaceutical composition which comprises the compound (I) of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a pharmaceutically acceptable carrier.
  • R 1 a hydrogen atom, a halogen atom or a lower alkyl group
  • R 2 a hydrogen atom, a hydroxyl group or a lower alkoxy group
  • X and Y the same or different from each other and each represents a bond, an oxygen atom (--O--), a carbonyl group (--CO--), a group represented by the formula --S(O) p -- or a group represented by the formula --NR 3 --,
  • R 3 a hydrogen atom or a lower alkyl group which may have a substituent
  • Z an oxygen atom (--O--), a group represented by the formula --S(O) q --, a carbonyl group (--CO--) or a group represented by the formula --NR 5 --,
  • R 4 a hydrogen atom, a halogen atom or a lower alkyl group
  • R 5 a hydrogen atom or a lower alkyl group
  • n the same or different from each other and each is 0 or an integer of 1 to 5,
  • n an integer of 1 to 5
  • the pharmaceutical composition as another object of the present invention is a pharmaceutical composition which contains a quinuclidine derivative represented by the general formula (I') or a pharmaceutically acceptable salt thereof as its active ingredient, a pharmaceutical composition which uses the compound (I') of the present invention having squalene synthase inhibiting activity as its active ingredient, a pharmaceutical composition as a cholesterol lowering agent which uses the compound (I') of the present invention having squalene synthase inhibiting activity as its active ingredient, particularly a pharmaceutical composition which uses the compound (I') of the present invention having squalene synthase inhibiting activity as its active ingredient and is a drug for use in the prevention or treatment of hyperlipemia, arteriosclerosis, aneurysm, ischemic heart diseases such as myocardial infarction, angina pectoris and the like and cerebral arteriosclerotic diseases such as cerebral infarction and the like.
  • R 1 a hydrogen atom
  • R 2 a hydrogen atom, a hydroxyl group or a lower alkoxy group
  • X and Y the same or different from each other and each represents a bond, an oxygen atom (--O--), a carbonyl group (--CO--), a group represented by the formula --S(O) p -- or a group represented by the formula --NR 3 --,
  • R 3 a hydrogen atom or a lower alkyl group which may have a substituent
  • Z an oxygen atom (--O--), a group represented by the formula --S(O) q --, a carbonyl group (--CO--) or a group represented by the formula --NR 5 --,
  • R 4 a hydrogen atom, a halogen atom or a lower alkyl group
  • R 5 a hydrogen atom or a lower alkyl group
  • n the same or different from each other and each is 0 or an integer of 1 to 5,
  • n an integer of 1 to 5
  • lower alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,
  • lower alkoxy group examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentyloxy, tert-pentyloxy, neopentyloxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy and the like, of which methoxy group and ethoxy group are particularly preferred.
  • halogen atom examples include fluorine, chlorine, bromine and iodine atoms, of which fluorine and chlorine atoms are preferred and fluorine atom is particularly preferred.
  • the saturated lower alkylene group is a straight or branched alkylene group having 1 to 6 carbon atoms, and its illustrative examples include methylene, ethylene, ethylidene, trimethylene, isopropylidene, propylene, tetramethylene, pentamethylene, hexamethylene and the like, of which alkylene groups having 1 to 4 carbon atoms are preferred.
  • Illustrative examples of the group represented by the formula --(CH 2 ) m Z(CH 2 ) n -- include --OCH 2 --, --CH 2 O--, --COCH 2 , --CH 2 CO--, --NHCH 2 --, --CH 2 NH--, --N(CH 3 )CH 2 --, --CH 2 N(CH 3 )--, --N(CH 2 CH 3 )CH 2 --, --CH 2 N(CH 2 CH 3 )--, --NHC(CH 3 ) 2 (CH 2 ) 5 --, --CH 2 OCH 2 --, --CH 2 COCH 2 --, --CH 2 NHCH 2 --, --CH 2 N(CH 3 )CH 2 --, --CH 2 NH(CH 2 CH 3 )CH 2 --, --CH 2 NHC(CH 3 ) 2 (CH 2 ) 5 --, --(CH 2 ) 2 O---, --(CH 2 ) 3 O---, --(CH 2 ) 4 O--, --(CH 2 ) 5 O-
  • Examples of the "substituent" of the lower alkyl group which may have a substituent of R 3 include a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group and an aryl group, and these substituents may be substituted at optional positions.
  • aryl group means a carbocyclic aryl group, and its illustrative examples include phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl, phenanthryl and the like, of which phenyl is particularly preferred.
  • the "mono- or di-lower alkylamino group” is a group in which an amino group is substituted with one or two of the aforementioned lower alkyl groups, and its illustrative examples include mono-lower alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentyl(amyl)amino, isopentylamino, neopentylamino, tert-pentylamino and the like and di-lower alkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino and the like, of which methylamino, ethylamin
  • the "lower alkoxycarbonyl group” means a carboxyl group which is substituted with one of the aforementioned lower alkoxy groups, and its illustrative examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxy(amyloxy)carbonyl, isopentyloxycarbonyl, tert-pentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1,2-dimethylpropoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl and the like, of which methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl groups are preferred, and ethoxycarbonyl group is particularly preferred.
  • the "mono- or di-lower alkylcarbamoyl group” is a carbamoyl group which is substituted with one or two of the aforementioned lower alkyl groups, and its illustrative examples include mono-lower alkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentyl(amyl)carbamoyl, isopentylcarbamoyl, neopentylcarbamoyl, tert-pentylcarbamoyl and the like and di-lower alkylcarbamoyl groups such as dimethylcarbamoyl, ethy
  • the compound (I) of the present invention may have an asymmetric carbon atom and a double bond.
  • various isomers such as optical isomers, geometrical isomers (cis-form and trans-form) and the like, either in isolated forms or as mixtures, are all included in the compound (I) of the present invention.
  • the compound (I) of the present invention may form acid addition salts or salts with bases. These salts are also included in the compound of the present invention.
  • Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid and the like and acidic amino acids such as aspartic acid, glutamic acid and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum and the like and organic bases such as methylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine,
  • the compound (I) of the present invention and salts thereof may be isolated as hydrates, various solvates such as ethanol solvate and the like or polymorphic forms thereof, and these various hydrates, solvates and polymorphic forms are also included in the compound of the present invention.
  • the compound of the present invention represented by the general formula (I) can be synthesized, for example, by the following methods, though production methods of the compound of the present invention are not restricted thereby.
  • novel intermediates are also included in the present invention, their production methods are also described in detail.
  • halogen atoms such as chlorine, bromine, iodine and the like and mesyloxy, tosyloxy and the like can be exemplified.
  • Method A In this method, 3-quinuclidinone (II) is subjected to the Wittig reaction (first step) to effect formation of a complex with borane (second step) which is isomerized (third step) to give an ester (V), the ester is subjected to a reduction reaction to give an alcohol (VII) (fourth step) and then the hydroxyl group of the alcohol (VII) is converted into a leaving group (fifth step), thereby obtaining a quinuclidine compound (VIII) which is a starting compound for the compound of the present invention.
  • the order of the first step and the second step may be changed.
  • the Wittig reaction is carried out in the conventional way.
  • 3-quinuclidinone hydrochloride may be used instead of 3-quinuclidinone (II). In that case, it is necessary to add the aforementioned base in an increased amount equivalent to hydrogen chloride.
  • the borane complex formation reaction is carried out by stirring the quinuclidine compound (III) and the reaction-corresponding amount of borane in the aforementioned organic solvent with ice-cooling.
  • the isomerization reaction is carried out by stirring the ester (IV) and the reaction-corresponding amount of the aforementioned base in an alcohol such as methanol, ethanol, isopropanol or the like at room temperature or with heating, preferably from room temperature to 50° C.
  • an alcohol such as methanol, ethanol, isopropanol or the like
  • the geometrical isomers are converted into alcohol by the subsequent reduction reaction (described hereinafter) and then separated easily by silica gel chromatography or the like.
  • the reduction reaction is carried out by stirring the ester (V) in the presence of the reaction-corresponding amount of a reducing agent (metal hydride such as diisobutylaluminum hydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride or the like) in an organic solvent inert to the reaction, such as toluene, THF, diethyl ether, hexane or the like at cooling temperature to room temperature, preferably at -78° C. to 0° C.
  • a reducing agent metal hydride such as diisobutylaluminum hydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride or the like
  • organic solvent inert such as toluene, THF, diethyl ether, hexane or the like
  • the leaving group conversion reaction is carried out by adding methanesulfonyl chloride and lithium chloride to the alcohol (VII) obtained in the above reduction reaction and stirring the mixture in the presence of an amine base (triethylamine or the like) in a solvent inert to the reaction, such as methylene chloride, dimethylformamide (DMF), THF, dioxane, diethyl ether or the like at room temperature.
  • an amine base triethylamine or the like
  • a solvent inert such as methylene chloride, dimethylformamide (DMF), THF, dioxane, diethyl ether or the like at room temperature.
  • Method B In this process, the starting material is subjected to Wittig reaction (first step), isomerized (second step) and then made into a complex with borane (third step), thereby obtaining the ester (V) which is subsequently converted into the quinuclidine compound (VIII) in the same manner as the case of Method A.
  • a borane-added form (X) of the compound of the present invention is obtained by subjecting the quinuclidine compound (VIII) and a hydroxy compound (IX) to alkylation reaction.
  • the alkylation reaction is carried out by stirring the quinuclidine compound (VIII) and the reaction-corresponding amount of a hydroxy compound (IX) in the presence of a base (potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or alkyl lithium such as n-butyl lithium, or the like) in an organic solvent inert to the reaction, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), THF, dioxane, diethyl ether, dimethoxyethane, acetone, acetonitrile or the like at room temperature.
  • a base potassium carbonate, sodium hydride or alkyl lithium such as n-butyl lithium, or the like
  • organic solvent inert
  • R 3a and R 3b are different from each other and each represents a group of R 3 other than a hydrogen atom.
  • the compound of the present invention is obtained by the elimination of borane, alkylation reaction when X is NH and conversion reaction of the substituent.
  • Elimination of borane This is carried out by stirring corresponding borane complex (X, XI or XII) at room temperature or with heating, in the presence of an acid (an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or the like, or an organic acid such as a carboxylic acid (e.g., acetic acid, oxalic acid or the like) or an organic sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid or the like) in an organic solvent inert to the reaction, such as an alcohol (e.g., methanol, ethanol, isopropanol or the like), THF, diethyl ether, DMF or the like.
  • an acid an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or the like
  • an organic acid
  • the free-form compound of the present invention (Ia, Ib or Ic) can be obtained by stirring at room temperature in the presence of a base (potassium carbonate aqueous solution, sodium bicarbonate aqueous solution, sodium hydroxide aqueous solution or the like).
  • a base potassium carbonate aqueous solution, sodium bicarbonate aqueous solution, sodium hydroxide aqueous solution or the like.
  • Alkylation This is carried out by stirring the borane complex (X) in which X is NH and the reaction-corresponding amount of an alkylating agent (a halogenoalkyl or the like) in the presence of a base (sodium hydride, potassium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate or alkyl lithium such as n-butyl lithium, methyl lithium, t-butyl lithium or the like) in an organic solvent inert to the reaction, such as DMF, DMSO, THF, dioxane, diethyl ether, dimethoxyethane, acetonitrile or the like at cooling temperature to room temperature, thereby obtaining the compound (XI) in which R 3 is a lower alkyl group which may have an aryl group, a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a carboxy group, a lower al
  • the substituent conversion reaction for example, the reaction from an amino-lower alkyl group to a mono- or di-lower alkylamino-lower alkyl group or from a carbamoyl group to a mono- or di-lower alkylcarbamoyl group, can be effected by a method similar to the above alkylation reaction.
  • carbazole compound (XI) or (XII) can be synthesized directly from the intermediate (VIII) by the second production method using the compound (IX) in which X is NR 3 .
  • the compound (Id) of the present invention is produced by the elimination of borane (deprotection) from an ether compound (XV) which is obtained by the alkylation of a borane-(3-quinuclidinol) complex (XIV) in the presence of a base.
  • the alkylation reaction can be effected by the same method of the second production method, and elimination of borane can be effected by the same method of the third production method.
  • a compound of the present invention represented by (Ie) can be produced by carrying out the same reaction using a borane- 3-(2-hydroxyethylidene)quinuclidine! complex (VII) instead of the alcohol (XIV) of the material compound.
  • the compound (If) of the present invention is produced by a reductive condensation reaction of an aromatic aldehyde (XVI) with 3-aminoquinuclidine (XVII).
  • This reaction is carried out by using the compound (XVI) and 3-aminoquinuclidine (XVII) in equivalent molar ratio or either one of them in an excess amount, and stirring them at room temperature or with heating, in an organic solvent inert to the reaction; such as dichloromethane, THF, methanol, ethanol, benzene or the like, water, or a mixture solvent thereof, in the presence of a reducing agent, or by subjecting the compound (VI) and the reaction-corresponding amount of 3-aminoquinuclidine (VII) to a condensation reaction without solvent or in a solvent such as benzene, toluene or the like while removing water under azeotropic condition or in the presence of a drying agent, thereby synthesizing a Schiff base, and then carrying out the
  • Preferred examples of the reducing agent to be used in this reaction include metal hydrides such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. Acid catalysts such as hydrochloric acid, acetic acid and the like may also be used.
  • a reductive condensation reaction of the amine compound (XVIII) with 3-quinuclidinone (II) may be used as an alternative method.
  • the reaction conditions, solvents and reducing agents can be set in the same manner as described above.
  • R is a lower alkyl group and D is a chlorine atom or a bromine atom.
  • the compound (Ig) of the present invention is produced by the following method using an aldehyde (XIX) as the material compound.
  • This production method is effected by allowing a dihalogenoolefin (XX) obtained by the Wittig reaction (first step) to react with 2 equivalents of an organic lithium reagent, and then allowing the resulting lithium acetylide (XXI) to react with 3-quinuclidinone (second step).
  • the Wittig reaction may be carried out by using a Wittig reaction agent prepared by mixing carbon tetrabromide, zinc (dust) and triarylphosphine such as triphenylphosphine or the like in dichloromethane, and allowing the agent to react with the aldehyde (XIX).
  • a Wittig reaction agent prepared by mixing carbon tetrabromide, zinc (dust) and triarylphosphine such as triphenylphosphine or the like in dichloromethane, and allowing the agent to react with the aldehyde (XIX).
  • Examples of the organic lithium reagent to be used in the second step include n-butyl lithium, methyl lithium, sec-butyl lithium, t-butyl lithium and the like, and examples of the reaction solvent include ethers such as THF, diethyl ether, dimethoxyethane and the like and inert solvents such as cyclohexane, hexane, pentane and the like.
  • the compound (Ig) of the present invention can be obtained with high yield by a method in which n-butyl lithium (2 equivalents) is added under cooling (--78° to 0° C.) to THF solution of the compound (XX), and the mixture is warmed to room temperature, cooled again and then allowed to react with 3-quinuclidinone added.
  • the compound (Ih) of the present invention is produced by allowing a metal enolate, which is formed by the reaction of a methyl aryl ketone (XXII) with a base, to undergo an aldol reaction with 3-quinuclidinone.
  • a metal enolate which is formed by the reaction of a methyl aryl ketone (XXII) with a base
  • metal amides such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and the like are used preferably.
  • the compound (XXII) is a phenothiazine derivative which has a lower alkyl substituent at the 10-position
  • the same mol equivalent of the base is required based on the compound (XXII)
  • two equivalents of the base is required based on the ketone (XXII) in the case of a phenothiazine derivative which has no substituent at the 10-position.
  • the reaction solvent include ethers such as THF, diethyl ether, dimethoxyethane and the like which are generally used in the aldol reaction of metal enolate.
  • various inorganic metal salts such as zinc chloride, magnesium chloride, titanium tetrachloride and the like are added to the lithium enolate or potassium enolate which is formed when the aforementioned base is used, and then the aldol reaction is carried out by adding 3-quinuclidinone.
  • the compound (I) of the present invention obtained in this manner is isolated and purified as its free form or as a salt thereof, a hydrate thereof, a solvate thereof or a polymorphic form thereof. Also, salts of the compound (I) of the present invention can be produced by subjecting the compound to usual salt forming reactions.
  • the isolation and purification are carried out by employing usual chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatographic techniques and the like.
  • optical isomers can be separated into stereochemically pure isomers by selecting an appropriate material compound or by racemic resolution of racemic compounds (for example, a method in which such compounds are converted into diastereomer salts with general optically active acids or bases and then subjected to optical resolution).
  • the compound (I) of the present invention a pharmaceutically acceptable salt thereof, a hydrate-thereof or a solvate thereof have excellent squalene synthase inhibiting activity and excellent cholesterol biosynthesis inhibiting action in the living body based on this activity. Also, since the compound is effective even in experiments in which human cultured cells are used, it is useful for the prevention or treatment of arteriosclerosis, aneurysm, ischemic heart diseases such as myocardial infarction, angina pectoris and the like and cerebral arteriosclerotic diseases such as cerebral infarction and the like, induced by the action of cholesterol in human and warm-blooded animals, particularly in human.
  • the compound of the present invention selectively inhibits squalene synthase which is an enzyme located at the middle stage of the cholesterol biosynthesis system, it shows extremely lowered side effects or shows no side effects which are common in inhibitors of enzymes located at the early stage or late stage of the cholesterol biosynthesis system, such as inhibition of the synthesis of important metabolic products such as dolichol, ubiquinone, isopentenyl tRNA, p21Ras, low molecular weight G protein and the like and generation of hepatic cytotoxicity (myopathy) caused by the accumulation of toxic substances such as desmosterol.
  • squalene synthase which is an enzyme located at the middle stage of the cholesterol biosynthesis system
  • the squalene synthase inhibiting action and cholesterol biosynthesis inhibiting action of the compound of the present invention have been confirmed by the following methods.
  • HepG2 cells Human hepatoma cells (HepG2 cells) were cultured using DMEM containing 10% FBS until a single layer was formed, and then the medium was replaced by DMEM supplemented with 10% human lipoprotein deficient serum (LPDS) to carry out 24 hours of culturing. The cells were washed twice with PBS, collected using a Rubber policeman and subjected to centrifugation. The resulting precipitate was homogenized in five volumes of 50 mM Hepes buffer (pH 7.5) containing 5 mM EDTA and centrifuged at 20,000 ⁇ g for 15 minutes. The supernatant was again subjected to the same centrifugation. The supernatant was subjected to 1 hour of centrifugation at 100,000 ⁇ g, and the microsomes obtained were suspended in the same buffer and used in the test as a HepG2 squalene synthase fraction.
  • LPDS human lipoprotein deficient serum
  • a dimethyl sulfoxide solution of each drug to be tested was added to a solution of the squalene synthase fraction prepared above (protein 10 ng, 50 mM Hepes buffer (pH 7.5)), 11 mM NaF, 5.5 mM MgCl 2 , 3 mM DTT, 1 mM NADPH, 1 mM pyrophosphate and 2.5 ⁇ M 3 H-FPP, and the mixture was adjusted to a total volume of 0.2 ml and shaken at 30° C. for 20 minutes to effect the reaction. The reaction was terminated by adding 100 ⁇ l of 20% potassium hydroxide-50% ethanol solution, and the reaction solution was heated at 65° C. for 30 minutes.
  • the un-saponified material was extracted with petroleum ether, and 1/3 volume thereof was subjected to measurement by a liquid scintillation counter.
  • the 3 H radioactivity of the un-saponified material was regarded as products down stream of squalene in the cholesterol biosynthesis system, and the squalene synthase inhibiting action was calculated by comparing 3 H radioactivities of the test group and control group.
  • concentration of each compound of the present invention to inhibit 50% of squalene synthase (IC 50 value) was obtained by calculation.
  • mice Male golden hamsters (130 to 150 g) which have been treated by reversing night and day since 12 or more days before the commencement of administration were divided into groups 4 days before the administration in such a manner that the cholesterol value became the same among the groups.
  • Each drug was prepared as a 0.5% methyl cellulose solution and administered by force in a dosage of 50 mg/kg. In this case, the liquid volume was 10 ml/kg.
  • the administration was carried out continuously for 4 days at around A.M. 11:00 under satiated condition and then on the fifth day after 16 hours of fasting. After 2 hours of the final administration, blood samples were collected from the abdominal vena cava under diethyl ether anesthesia and their cholesterol values were measured using an automatic analyzer (Hitachi 736).
  • the IC 50 value of squalene synthase inhibiting activity was calculated by the aforementioned test method (A), with the results shown in Table 1.
  • each compound of the present invention showed strong activity to inhibit squalene synthase prepared from human hepatoma cells.
  • the compounds of the present invention showed clear inhibiting action also in the rat squalene synthase inhibition test within the concentration range of approximately from 0.01 to 25 ⁇ M.
  • the cholesterol lowering action was measured by the aforementioned test method (C), with the results on the lowering ratio shown in Table 2.
  • the compounds of the present invention showed strong action to lower cholesterol level.
  • the compounds of the present invention showed strong activity to inhibit human squalene synthase and strong action to lower cholesterol level in hamster.
  • the compounds of the present invention are useful for the treatment or prevention of various diseases induced by the action of cholesterol (arteriosclerosis, aneurysm, ischemic heart diseases such as myocardial infarction, angina pectoris and the like and cerebral arteriosclerotic diseases such as cerebral infarction and the like).
  • the pharmaceutical composition which contains one or two or more of the compound (I) of the present invention, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof as the active ingredient is prepared into tablets, powders, fine powders, granules, capsules, pills, solutions, injections, suppositories, ointments, adhesive preparations and the like using generally used pharmaceutical carriers, excipients and other additives and administered orally (including sublingual administration) or parenterally.
  • Clinical dose of the compound (I) of the present invention in human is appropriately decided by taking symptoms, age, sex and the like of each patient to be treated into consideration, but the compound may be administered orally generally within the range of from 10 mg to 500 mg, preferably from 100 mg to 500 mg, per day per adult, by dividing the daily dose into one to several doses per day, or within the range of from 1 mg to 100 mg, preferably from 10 mg to 100 mg, per day per adult, by intravenous administration by dividing the daily dose into one to several doses per day, or by continuous intravenous administration within the range of from 1 hour to 24 hours per day.
  • a smaller dosage than the above range may be sufficient enough in some cases.
  • the solid composition for use in the oral administration according to the present invention is used in the form of tablets, powders, granules and the like.
  • one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or aluminum magnesium metasilicate.
  • the composition may contain additives other than the inert diluent, such as lubricants (e.g., magnesium stearate or the like), disintegrating agents (e.g., calcium cellulose glycolate or the like), stabilizing agents (e.g., lactose or the like), and solubilization assisting agent (e.g., glutamic acid, aspartic acid or the like).
  • lubricants e.g., magnesium stearate or the like
  • disintegrating agents e.g., calcium cellulose glycolate or the like
  • stabilizing agents e.g., lactose or the like
  • solubilization assisting agent e.g., glutamic acid, aspartic acid or the like.
  • tablets or pills may be coated with a film of a gastric soluble or enteric soluble substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like.
  • the liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent such as purified water or ethanol.
  • this composition may also contain auxiliary agents such as a solubilizing or solubilization assisting agent, a moistening agent, a suspending agent and the like, as well as sweeteners, flavors, aromas and antiseptics.
  • the injections for parenteral administration includes aseptic aqueous or non-aqueous solutions, suspensions and emulsions.
  • aqueous solutions and suspensions include distilled water for injection use and physiological saline.
  • non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, plant oils (e.g., olive oil or the like), alcohols (e.g., ethyl alcohol or the like), polysorbate 80 (trade name) and the like.
  • Such a composition may further contain additive agents such as a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilizing or solubilization assisting agent.
  • additive agents such as a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilizing or solubilization assisting agent.
  • additive agents such as a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilizing or solubilization assisting agent.
  • a mixture of sodium bis(2-methoxyethoxy)aluminum hydride (70 wt. % toluene solution, 425 g, 1.47 mol) and toluene (800 ml) was added dropwise (2.5 hours) to a mixture of borane- ethyl fluoro-(3-quinuclidinylidene)acetate! complex (304 g, E/Z mixture) and toluene (800 ml) while keeping the inner temperature at -45° to -35° C., and the mixture was stirred for additional 1 hour.
  • a 2N sodium hydroxide aqueous solution (1.5 l) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • reaction mixture was concentrated under a reduced pressure, ethyl acetate and saturated sodium chloride aqueous solution (60 ml for each) were added to the resulting residue in that order, and the reaction product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to give the title compound (7.40 g, 17.7 mmol, 99%) as brown oil.
  • sodium hydride 60 wt. %, 0.19 g, 4.79 mmol
  • sodium hydride 60 wt. %, 0.19 g, 4.79 mmol
  • a mixture of borane- (Z)-3- 2- 9-(2-hydroxyethyl)carbazol-2-yloxy!ethylidene!quinuclidine! complex (1.20 g, 3.19 mmol) and DMF (16 ml)
  • Methyl iodide (0.30 ml, 4.79 mmol) was added and the mixture was stirred for 1 hour.
  • reaction mixture was concentrated under a reduced pressure, ethyl acetate and saturated sodium chloride aqueous solution (each 30 ml) were added to the resulting residue in that order, and then the reaction product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to give the title compound (1.24 g, 3.18 mmol, 100%) as colorless crystals.
  • N-Methylformanilide (5.35 ml, 43.6 mmol) and phosphorus oxychloride (4.06 ml, 43.6 mmol) were added at room temperature to a mixture of 10-ethylphenothiazine (7.62 g, 33.5 mmol) and 1,2-dichlorobenzene (34 ml), and the mixture was stirred at 100° C. for 24 hours.
  • a sodium acetate aqueous solution 45 wt. %, 85 g was added to the reaction mixture, which was subsequently concentrated under a reduced pressure.
  • methanesulfonyl chloride (3.9 ml, 50 mmol) was added dropwise to a mixture of 3-hydroxy-10-methylphenothiazine (10.9 g, 45 mmol), triethylamine (8.2 ml, 59 mmol) and dichloromethane (80 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the reaction product was extracted with chloroform.
  • the extract was washed with a saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to give the title compound (8.09 g, 30.9 mmol, 69%) as yellow crystals.
  • the compound of Reference Example 22 was obtained in the same manner as in Reference Example 21.
  • the reaction product was extracted from the insoluble matter three times with hexane (about 60° C.), and the thus collected organic layers were combined and concentrated under a reduced pressure.
  • the extract was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure.
  • the compound of Reference Example 27 was obtained in the same manner as in Reference Example 26.
  • the compound of Reference Example 33 was obtained in the same manner as in Reference Example 32.
  • the compound of Reference Example 35 was obtained in the same manner as in Reference Example 34.
  • sodium diisobutyl aluminum hydride (1.01M toluene solution, 634 ml, 640 mmol) was added dropwise to a mixture of borane- ethyl (Z)-fluoro-(3-quinuclidinylidene)acetate! complex (66.1 g, 291 mmol, E/Z mixture) and toluene (200 ml) spending 1.5 hours, and the mixture was stirred for 0.5 hour.
  • Methanol (60 ml), ethyl acetate (500 ml) and water (500 ml) were added to the reaction mixture in that order and the mixture was stirred at room temperature.
  • the compound of Reference Example 38 was obtained in the same manner as in Reference Example 25.
  • the resulting crystals were added to a mixture of potassium carbonate (200 g), water (800 ml) and chloroform (1.2 l), the mixture was stirred at 50° C. for 1 hour, and the crystals were collected by filtration (72.1 g). They were combined with other portion of crystals (22.2 g) obtained by extraction of the filtrate with chloroform, and the combined crystals, 94.1 g in total; were recrystallized from dioxane to give the title compound 84.5 g, 251 mmol, 83%).
  • sodium hydride 60 wt. %, 0.15 g, 3.83 mmol
  • sodium hydride 60 wt. %, 0.15 g, 3.83 mmol
  • a mixture of borane- (Z)-3- 2-(9-methylcarbazol-2-yloxy)ethylidene!quinuclidine! complex (1.06 g, 3.19 mmol) and DMF (9 ml)
  • Methyl iodide (0.24 ml, 3.83 mmol) was added, and the mixture was again stirred for 1 hour.
  • Example 12 The following compound of Example 12 was obtained in the same manner as in Example 11.
  • Acetone (150 ml) and a hydrogen chloride ethanol solution (ca. 5M, 60 ml) were added to the resulting residue in that order, and the mixture was stirred for 20 minutes and then concentrated under a reduced pressure.
  • a potassium carbonate-aqueous solution (ca. 30 wt. %, 280 g) was added to the residue.
  • the reaction product was extracted with chloroform, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure.
  • This was dissolved in ethyl acetate (100 ml), 4N hydrogen chloride-ethyl acetate (7.5 ml) was added, and the thus precipitated crystals were collected by filtration to give the title compound (9.05 g, 24.3 mmol, 41%) as colorless crystals.
  • a hydrogen chloride ethanol solution (ca. 5M, 1 ml) was added to a mixture of borane- 3-(10-ethylphenothiazin-3-ylmethoxy)quinuclidine! complex (1.28 g, 3.37 mmol) and acetone (5 ml), and the mixture was stirred for 30 minutes.
  • Triethylamine (2 ml) was added to the reaction mixture, and the mixture was concentrated under a reduced pressure.
  • Chloroform and a 2N sodium hydroxide aqueous solution (each 30 ml) were added to the resulting residue in that order, and then the reaction product was extracted with chloroform.
  • sodium triacetoxy borohydride (1.24 g, 5.85 mmol) was added to a mixture of 3-aminoquinuclidine (405 mg, 3.21 mmol), 3-formyl-10-methylphenothiazine (704 mg, 2.92 mmol), acetic acid (1.8 ml) and methylene chloride (29 ml), and the mixture was stirred for 1 hour.
  • a saturated sodium bicarbonate aqueous solution (30 ml) was added to the reaction mixture and the reaction product was extracted with chloroform.

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US20030105089A1 (en) * 2001-09-12 2003-06-05 Wishka Donn G. Substituted 7-aza[2.2.1]bicycloheptanes for the treatment of disease
JP2005512974A (ja) * 2001-10-17 2005-05-12 ユ セ ベ ソシエテ アノニム キヌクリジン誘導体、その調製方法、及びｍ２及び／又はｍ３ムスカリン受容体阻害剤としてのその使用
US20050107025A1 (en) * 2001-11-20 2005-05-19 Malcolm Reginald H.B. Coin handler
US6951868B2 (en) 2001-11-09 2005-10-04 Pfizer Inc. Azabicyclic-phenyl-fused-heterocyclic compounds for treatment of disease

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Publication number Priority date Publication date Assignee Title
US7365193B2 (en) 2004-02-04 2008-04-29 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
KR20200100081A (ko) 2017-11-20 2020-08-25 실리콘 스왓, 인크. 옥소아크리디닐 아세트산 유도체 및 사용 방법
US11414387B2 (en) 2017-11-20 2022-08-16 Stingthera, Inc. Oxoacridinyl acetic acid derivatives and methods of use

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WO1993015073A1 (en) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Azabricyclic compounds as calcium channel antagonists
US5654315A (en) * 1991-12-23 1997-08-05 Imperial Chemical Industries Plc Quinuclidine compounds useful in treating diseases

Patent Citations (2)

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US5654315A (en) * 1991-12-23 1997-08-05 Imperial Chemical Industries Plc Quinuclidine compounds useful in treating diseases
WO1993015073A1 (en) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Azabricyclic compounds as calcium channel antagonists

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030105089A1 (en) * 2001-09-12 2003-06-05 Wishka Donn G. Substituted 7-aza[2.2.1]bicycloheptanes for the treatment of disease
JP2005512974A (ja) * 2001-10-17 2005-05-12 ユ セ ベ ソシエテ アノニム キヌクリジン誘導体、その調製方法、及びｍ２及び／又はｍ３ムスカリン受容体阻害剤としてのその使用
US7361668B2 (en) * 2001-10-17 2008-04-22 Ucb, S.A. Quinuclidine derivatives processes for preparing them and their uses as m2 and/or m3 muscarinic receptor inhibitors
US6951868B2 (en) 2001-11-09 2005-10-04 Pfizer Inc. Azabicyclic-phenyl-fused-heterocyclic compounds for treatment of disease
US20050107025A1 (en) * 2001-11-20 2005-05-19 Malcolm Reginald H.B. Coin handler

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WO1996026938A1 (en) 1996-09-06
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HUP9801361A3 (en) 1998-10-28
AU4844096A (en) 1996-09-18
CN1177353A (zh) 1998-03-25
EP0812840A1 (de) 1997-12-17
HUP9801361A2 (hu) 1998-09-28
PL322083A1 (en) 1998-01-05
CA2213706A1 (en) 1996-09-06
EP0812840A4 (de) 1999-02-10
AU696626B2 (en) 1998-09-17

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